SOLUBILITY OF DRUGS

Ms. Poonam.D.Dighe
Amrutvahini College of Pharmacy,
Sangamner
 SOLUBILITY
“ The concentration of a substance (solute) that
dissolves in a given volume of solvent at a certain
temperature to form a homogenous solution.”
OR
“ The spontaneous interaction of or more
two
substances to form a homogenous molecular
dispersion.”

A “soluble An “insoluble
substance” substance”

2
 Solubility
•Substances fall into three main categories of
solubility:

•Generally, a substance is considered “soluble” if it

dissolves into solution completely.

•“Sparingly (or slightly) soluble” substances are partially

soluble. A limited amount of substance dissolves.

•“Insoluble” substances do not dissolve at all (or a very

•tiny amount dissolves.)
Solubility Expressions
+

Definitions
Solution: is a mixture of two or more components that form a homogenous
mixture. The components are referred to the solute and/or solutes & the
solvent and/or solvents .
 Solute: is the dissolved agent . (less abundant part of the solution )
 Solvent : is the component in which the solute is dissolved (more abundant
part of the solution).
 Dilute Solutions: A solution containing relatively small quantity of solute as
compared with the amount of solvent.
 Concentrated Solution: A solution containing large amount of solute in the
solution than that in dilute solution.
 A saturated solution: is one in which an equilibrium is established between
dissolved and undissolved solute at a definite temperature. Or A solution that
contains the maximum amount of solute at a definite temperature
 An unsaturated solution: or subsaturated solution is one containing the
dissolved solute in a concentration below that necessary for complete
saturation at a definite temperature.
+
Solubility

 A supersaturated solution: contains more of the dissolved solute

than it would normally contain in a saturated state at a definite
temperature.

Solubility:

 In a quantitative way: it is the concentration of solute in a saturated

solution at a certain temperature

 In a qualitative way: it is the spontaneous interaction of two or more

substances (solute & solvent) to form a homogeneous molecular
dispersion
+
Degree of saturation

Unsaturated, Saturated or Supersaturated?

 How much solute can be dissolved in a solution?

+
Solubility Curve

 Any solution can be made saturated, unsaturated, or

supersaturated by changing the temperature.
 Types of Solutions: Based on
physical states of solute and
solvent:

Gas Gas Solid Smoke in air

Gas liquid Water vapors in air
 Electrolytes and Non Electrolytes Solutions
• Non Electrolyte: These are substances that do not yield
ions when dissolved in water & therefore do not
conduct an electric current through the solution.
• Ex. Sucrose, Glycerine, Urea.

• Electrolytes : These are substances that forms ions

when dissolved in water & therefore conduct an
electric current through the solution.
• Ex. HCL, Na Sulphate, ephedrine, phenobarbital.

• Electrolytes divided into strong electrolyte and weak

electrolytes
 Ideal and Real Solution

• Ideal Solution: is one in which there is no change in

properties of components other than dilution when
they are mixed to form the solution.
• Ex. 100ml methanol mixed with 100ml ethanol final
volume of the solution is 200ml.

• Real Solution: is the solution there is change in

properties of components when they are mixed to
form the solution.
• Ex. 100ml sulphuric acid mixed with 100ml water
final volume of solution is 180ml.
 % Concentration
The concentration of a solution is defined as the amount of solute
present in a given amount of solution.
mass solute
x
% (w/w) = mass solution 100

% (w/v) = mass solute

x
volume solution 100
% (v/v) =
volume solute
x
volume solution 100
 %
w/w:
It expresses the no. of grams of the solute per 100
gram of the solution.

e.g. a 10 % w/w aqueous glycerine solution means 10 g

of glycerine dissolved in sufficient water to make
overall 100 gram of the solution.
 %
v/v:
It expresses the no. of milliliters of the solute per 100
milliliters of the solution.

e.g. a 10 % v/v aqueous ethanolic solution means 10 ml

of ethanol dissolved in sufficient water to make
overall 100 mls of the solution.
 %
w/v
It expresses the no. of grams of the solute per 100
mls of the solution.

e.g. a 10 % w/v aqueous Nacl solution means 10 g of

Nacl dissolved in sufficient water to make overall 100
mls of the solution.
 %
v/w
It expresses the no. of mls of the solute per 100 gram
of the solution.

e.g. a 10 % v/w aqueous glycerine solution means 10

ml of glycerine dissolved in sufficient water to make
overall 100 gram of the solution.
Parts per Million
and Parts per
Billion
This is another way to expressing concentration,
particularly those of very dilute solutions. e.g. to
express the impurities of substances in water.
ppm denotes the amount of given substance in a total
amount of 1,000,000 of solution e.g. one milligram
per kilogram. 1 part in 10 6
ppb denotes the amount of given substance in a total
amount of 1,000,000,000 of solution e.g. 0.001
milligram per kilogram. 1 part in 10 9
 Parts per Million
and Parts per
Billion
Parts per Million (ppm)
ppm = mass of A in solution
total mass of solution  106

Par ts per Billion (ppb)

ppb = mass of A in solution
total mass of solution  109
 Molarity (M)
It expresses the no. of moles of solute
dissolved per liter of the solution.

mole of solute
M=
L of
solution
molarity= Given weight / molecular weight substance x
1/ volume of solution in liters

e.g.1 mole of Nacl= 58.5 gm of Nacl

No. of moles= Given weight / molecular weight
substance
Because volume is temperature dependent, molarity can
 Molality
(m)
It expresses the no. of moles of solute dissolved
per kg of the solvent.

moles of solute
m=
kg of
solvent
Because both moles and mass do not
change with temperature, molality
(unlike molarity) is not temperature
dependent.
Changing Molarity to Molality

If we know the
density of the
solution, we can
calculate the
molality from the
molarity, and
vice versa.
Normality
(N)
It expresses the no. of gram equivalent of solute
dissolved per liter of the solution.

N= No. gram equivalent of

solute L of solution
Normality= Given weight / equivalent weight x 1/
volume of solution in liters
EQUIVALENT WEIGHT

The no. of parts by weight of that substance that will

combine with one part by weight of replaceable H+ or
OH- or number of positive charge on elements
 Mole Fraction
The ratio of(X)
the number of the moles of that
component to the total number of moles of all the
components of the solution

moles of A
XA =
total moles in
solution
The sum of the mole fractions of all the components
is always equal to unity i.e. 1
 SOLUBILITY EXPRESSIONS
 The USP lists the solubility of drugs as: the number of ml of solvent in which
1g of solute will dissolve.
 E.g. 1g of boric acid dissolves in 18 mL of water, and in 4 mL of
glycerin.
 Substances whose solubility values are not known are described by the
following terms:
Sr. Description forms Parts of solvent required
No. ( Solubility) for one part of solute
1 Very soluble (VS) <1
2 Poorly soluble (PS) 1-10
3 Soluble 10-30
4 Sparingly soluble (SPS) 30-100
5 Slightly soluble (SS) 100-1000
6 Very slightly soluble (VSS) 1000-10000
7 Practically insoluble (PI) >10000 2
5
+ Solvent - Solute
Interactions
 In pre -(Solubility Process)
or early formulation, selection of the most suitable solvent is
based on the principle of

“like dissolves like”

 That is, a solute dissolves best in a solvent with similar chemical
properties. Or two substances with similar intermolecular forces are
likely to be soluble in each others
 Polar solutes dissolve in polar solvents. E.g salts & sugar dissolve in
water .
 Non polar solutes dissolve in non polar solvents. Eg. naphtalene
dissolves in benzene.
 +
POLAR SOLUTE - POLAR
SOLVENT
Ammonia Dissolves in Water:

 Polar ammonia molecules dissolve in polar water molecules.

 These molecules mix readily because both types of molecules

engage in hydrogen bonding.

 Since the intermolecular attractions are roughly equal, the

molecules can break away from each other and form new
solute (NH3), solvent (H2O) hydrogen bonds.
 Alcohol Dissolves in Water:

 The -OH group on alcohol is polar and mixes with the

polar water through the formation of hydrogen bonds.

 A wide variety of solutions are in this category such as sugar

in water, alcohol in water, acetic and hydrochloric acids.
Solute-Solvent interactions
+ Solute-Solvent
interactions
 If the solvent is A & the solute is B, and the forces of attraction are represented by
A-A, B-B and A-B,

One of the following conditions will occur:

1. If A-A >> A-B The solvent molecules will be attracted to each

other & the solute will be excluded. Example: Benzene & water, where benzene
molecules are unable to penetrate the closely bound water aggregates.

2. If B-B >> A-A The solvent will not be able to break the binding
forces between solute molecules. Example NaCl in benzene, where the NaCl
crystal is held by strong electrovalent forces which cannot be broken by
benzene.

3. If A-B >> A-A or B-B, or the three forces are equal The solute will .
form a solution. Example: NaCl in water.
+
Classification of solvents & their mechanism of
action

1. Polar
solvents

2. Non polar
solvents

3. Semi polar
solvents
+ Polar
solvents
 The solubility of a drug is due in large measure to the polarity of the solvent,
that is, to its dipole moment. Polar solvents dissolve ionic solutes and other
polar substances.

 The ability of the solute to form hydrogen bonds is a far more significant
factor than is the polarity as reflected in a high dipole moment

Water dissolves phenols, alcohols and other oxygen & nitrogen containing
compounds that can form hydrogen bonds with water.
+ Polar
solvents
 The solubility of a substance also depends on structural features such
as the ratio of the polar to the nonpolar groups of the molecule.

 As the length of a nonpolar chain of an aliphatic alcohol increases, the

solubility of the compound in water decreases

 Straight-chain monohydroxy alcohols, aldehydes, ketones, and acids

with more than four or five carbons cannot enter into the hydrogen-
bonded structure of water and hence are only slightly soluble.
+Polar solvents
 When additional polar groups are present in the molecule, as found
in propylene glycol, glycerin, and tartaric acid, water solubility
increases greatly.

Branching of the carbon chain reduces the nonpolar effect and leads to increased water
solubility.
Tertiary butyl alcohol is miscible in all proportions with water, whereas n-butyl alcohol
dissolves to the extent of about 8 g/100 mL of water at 20°C.

tert-Butanol n-Butanol
+

Hydrogen bonding is the attractive

interaction of a hydrogen atom with an
electronegative atom, such as nitrogen,
oxygen

Dipole-dipole forces are electrostatic interactions of

permanent dipoles in molecules.
 +
Non polar solvents
 Non-polar solvents are unable to reduce the attraction between the
ions of strong and weak electrolytes because of the solvents' low
dielectric constants.

 They are unable to form hydrogen bonds with non electrolytes.

 Non polar solvents can dissolve non polar solutes through weak van der
Waals forces

 Example: solutions of oils & fats in carbon tetrachloride or benzene.

Polyethylene glycol 400

Castor oil
 +
Semi polar solvents

 Semi polar solvents, such as ketones can induce a certain degree of

polarity in non polar solvent molecules. For example, benzene, which
is readily polarizable, becomes soluble in alcohol

 They can act as intermediate solvents to bring about miscibility of

polar & non polar liquids.

Example: acetone increases solubility of ether in water.

Propylene glycol has been shown to increase the mutual solubility of

water and peppermint oil and of water and benzyl benzoate
 MECHANISM OF SOLUTE SOLVENT INTERACTIONS
“LIKE DISSOLVES LIKE”
Sr. Nature of Mechanism of solubility Example
No Solvent
1. Polar a. High dielectric Water+ ethanol
constant
b. H- bond
formation
c. dipole
interactions

2. Non-polar weak van der waal’s Fats, oils, alkaloidal

forces bases + CCL4,
benzene
3. Semi-polar induce certain degree of Acetone increase
polarity solubility of ether in 3
water 8
 IDEAL SOLUBILITY PARAMETERS
‘Ability of a liquid to act as a solvent’
1) Hildebrand solubility parameter (δ) Based on
• It is total Vanderwaals force.
• The solubility parameter is a numerical value that indicates the
relative solvency behavior of a specific solvent.
• It is derived from the cohesive energy density of the solvent,
which in turn is derived from the heat of vaporization.
“cohesive energy density”
C= △Hv- RT/ Vm
Where C=Cohesive energy density
△Hv=Heat of Vaporization
R= Gas Constant T= Temperature Vm= Molar volume3
9
 Hildbrand Solubility Parameter

• In 1936 Joel H. Hildbrand proposed the square root of

the cohesive energy density as a numerical value
indicating the solvency behavior of a specific solvent
• The quantity represented by the symbol δ

• δ=√c= √△Hv- RT/ Vm

• The term hildbrands be adopted for solubility parameter
units, in order to recognize the tremendous contribution
that Dr. Hildbrand has made to solubility theory.
• Values shown in calories/cc, and Pascal.
• Example Water=23.5, n Pentane=7.0
 Hansen solubility parameter (δt)

• The most widely accepted three component system to

date is the three parameter system developed by Charles
M. Hansen in 1966.
• Hansen parameter divide the total Hildbrand value into
three parts:
• 1.Dispersion Force component
• 2.A H bond component
• 3. A Polar component
• δt= δd + δp + δh
• δ t= Total Hildbrand component
• δ d= Dispersion compomemt
• δ p= Polar Component
• δh = H bond component
• Example : Water=47.8 n Pentane=14.5
 Solvation / Dissolution
“ Interaction of a solute with the solvent, which leads
to stabilization of solute species in the solution”
+ve solvation energy= endothermic dissolution
-ve solvation energy= exothermic dissolution

4
2
 Association
“ Chemical reaction in which the opposite electric
charge ions come together in solution & form a
distinct chemical entity”
Classification according to nature of interaction:
1. Contact
2. Solvent shared
3. Solvent separated

4
3
 FACTORS INFLUENCING SOLUBILITY
1. Temperature
2. Nature of solvent ( like dissolves like)
3. Pressure
4. pH
5. Particle size
6. Crystal structure
7. Molecular structure
8. Solute- solvent interactions
9. Addition of substituent
10. Common ion effect
11. Solubilizing agents 9
 Solubility Curves
• A curve between solubility & temp. is termed
solubility curve.
• Normally temp. affect the solubility of any substance.
• In process…
• if heat is absorbed (△H is +ve) then solubility &
temp. increases.
• If heat is given out (△H is -ve) then decrease in
solubility & increase in temp.
• If heat is neither absorbed nor given out then
solubility is not affected by temp.

• Solubility curves are TWO types:

1. Continuous solubility curve
Continuous
solubility
curve

Discontinuous
solubility
curve
DIFFUSION PRINCIPLES IN BIOLOGICAL SYSTEMS
DIFFUSION:
“Mass transfer of individual molecules of a substance caused
by random molecular motion, associated with a driving
force such as the concentration gradient”
OR
“ A physical process that refers to the
net movement of molecules from
a region of high concentration to
lower concentration under the
influence of concentration
gradient.”
The particles The particles
They slowly The particles
are separate are fully
start to mix due are now nearly
when first diffuse.
to their fully diffuse.
put together. random
motion.
LAWS OF DIFFUSION
Derived by Adolf Fick in 1856.
FICK’S FIRST LAW OF DIFFUSION:
“Diffusion flux is directly proportional to
concentration
gradient under the assumption of steady state diffusion”
J= -D dc/dx
Where,
J= diffusion fl ux (g/ sq. cm/s)
D= Diffusion coefficient or
diffusivity ( cm sq/sec)
dc= change in concentration of material
( g/cubic cm)
dx= change in distance (cm) nit
Diffusion fl ux (J) is mass transfer through a
u Cross section area in unit time.
FICK’S SECOND LAW OF DIFFUSION:
“Change in concentration with time in a particular
region is proportional to the change in
concentration gradient at that point in the system.”

dc/dt = -dJ/dx
 • Diffusion in Biological Systems
• Drug molecule pass through living membrane by
• 1.Passive Diffusion- High to Low conc.
• 2.Active Diffusion – Low to High
conc.(Enzymes/Carrier)
• (Poor absorption through GIT)
• Rate of drug influenced by:
1. Physicochemical properties of the drug
2. Nature of the membrane
3. Conc. of drug across the membrane
• Most are Weak acidic or weak basic.
• Drugs in aqueous solution – ionized/unionized form
 • Diffusion in Biological Systems
• Percutaneous absorption of drug through the skin
steps
• 1.Dissolution of drug in the vehicle
• 2.Diffusion of the dissolved drug from the vehicle to
the surface of the skin
• 3.Penetration of drug molecule through the skin layer
• Steps control the permeation of drug into systemic
circulation
• Factors affect the permeation of the drug molecule
into skin:
1. Concentration of dissolved drug
2. Partition coefficient between skin and vehicle
 Dissolved substances have to pass
through the partially permeable cell
membrane to get into or out of a cell.
Diffusion is one of the processes that allows
this to happen..
 All living cells rely on diffusion to live.
They use it for:

• 

Getting raw materials for

respiration (dissolved
substances
 Removing waste products and gases)
(eg. from respiration)
Plants use of photosynthesis (raw materials
in, waste products out)

Examples…
 Oxygen in inhaled air diffuses
through the lungs and into the
bloodstream. The oxygen is then

transported throughout the body.

Carbon dioxide is the waste gas produced by respiration.

Carbon dioxide diffuses from body tissues into the
bloodstream and is exhaled via the lungs.

Where does gas exchange take place in the lungs?

 Measurement of Diffusion
• Franz Diffusion cell are used
to measure diffusion. In
short, diffusion is the
physical flow of material.

Application:
1. Release of drug from dosage form
2. To predict molecular weight of polymer
3. Absorption of drug through skin/GIT-tissue-excretion
4. Dialysis, microfiltration, ultrafiltration, haemodialysis,
somosis – principle diffusion
+ Types of
solutions
Solutions of pharmaceutical importance include:

 Gases in liquids

 Liquids in liquids

 Solids in liquids
 SOLUBILITY OF GASES IN LIQUIDS
Henry’s law:
‘Solubility is directly proportional to partial pressure
of gas at a constant temperature’.
S= KP

58
+
Solubility of gases in
liquids

When the pressure above the

solution is released (decreases),
the solubility of the gas
decreases

As the temperature increases the

solubility of gases decreases
 FACTORS INFLUENCING SOLUBILITY OF GASES IN LIQUIDS

1. Pressure
2. Temperature
3. Presence of Salts
4. Chemical interaction with the solvent
Application :
1. Preparation of Reagents
2. Preparation of Carbonated beverages
3. Solubility of oxygen in blood
4. Transportation of anesthetic gas through blood

9
 SOLUBILITY OF LIQUIDS IN LIQUIDS
1. Completely miscible liquids:
E.g. Water+ ethanol, Glycerine+ Alcohol, benzene+ CCL4

2. Partially miscible liquids:

E.g. Phenol+ water.

3. Completely immiscible liquids:

E.g. Mercury+ water.

61
 +Solubility of liquids in liquids

 Preparation of pharmaceutical solutions involves mixing of 2 or more liquids

 Alcohol & water to form hydroalcoholic solutions
 volatile oils & water to form aromatic waters
 volatile oils & alcohols to form spirits , elixirs

Liquid-liquid systems may be divided into 2 categories:

1. Systems showing complete miscibility such as alcohol & water, glycerin & alcohol,
benzene & carbon tetrachloride. These liquids also known as binary liquids

2. Systems showing Partial miscibility as phenol and water; two liquid layers are
formed each containing some of the other liquid in the dissolved state.

The term miscibility refers to the mutual solubility of the components in liquid-liquid
systems.
+
Solubility of liquids in liquids

 Complete miscibility occurs when: The adhesive forces between

different molecules (A-B) >> cohesive forces between like molecules
(A-A or B-B).

 Polar and semipolar solvents, such as water and alcohol, glycerin

and alcohol, and alcohol and acetone, are said to be completely
miscible because they mix in all proportions.

 Nonpolar solvents such as benzene and carbon tetrachloride are

also completely miscible.
 +
Solubility of liquids in liquids

 Partial miscibility results when: Cohesive forces of the constituents of a mixture

are quite different, e.g. water (A) and hexane (B). A-A » B-B.

 When certain amounts of water and ether or water and phenol are mixed, two
liquid layers are formed, each containing some of the other liquid in the
dissolved state.

 The effect of temperature on the miscibility of two-component liquids is

expressed by phase diagrams.

 In the phase diagrams of two-component liquids, the mixture will have an upper
critical solution temperature, a lower critical solution temperature or both.
 In cases of Partial miscibility

•Degree of miscibility may be dependent on the temperature

1. Solubility  with  in temperature (water-phenol)

2. Solubility  with  in temperature (water-
triethylamine)
3. Solubility  with  &  in temperature (water-
nicotine)
4. Solubility not affected by temperature

• In case of three component system the third liquid may

influence the degree of solubility of the 2 liquid system.
 SOLUBILITY OF SOLIDS IN LIQUIDS
• Some Important terms:
• 1.Solution
• 2.Solubility- Quantitative terms and
• Qualitative terms
• 3. Saturated Solution
• 4.Unsaturated Solution
• 5. Supersaturated Solution

• Applications:
1. Solubility of drugs in water and hydroalcoholic
solution is necessary for MFG.
2. IV,IM & SC injections are prepared by dissolving
drugs in solvents.
 Applications….
• 3. Solubility of drugs in GIF is an important step for
better absorption of drugs.
• 4. The action of a drug can be severely limited by
poor aqueous solubility.
• 5. The release and absorption of drug depends on
the degree of saturation of drug in the solvent.
• 6. Information of intermolecular forces of
interaction.
• 7. Crystallization of drugs from solvents.
• 8. Standard test for purity.
• 9. Determination of physicochemical properties.
• 10. Extraction and purification.
 FACTORS INFLUENCING SOLUBILITY OF DRUGS
• Solute Related:
• Nature of Solute- Size, Shape & Surface area
• Physicochemical Properties- MP, Molar
volume, pKa, molar volume.
• Physical forms- salt, crystalline state &
polymorphism
• Solvent related:
• Nature of solvent-Polarity, pH of medium,
volume of solvent.
• Environmental related factors:
• Temperature & Pressure
• Formulation related factors
 METHODS USED FOR DETERMINATION OF
SOLUBILITY:

1. Evaporation Method

2. Volumetric Method

3. Gravimetric Method

4. Instrumental Method
 COLLIGATIVE PROPERTIES
• Greek Word Colligatus- Collected together
• Defined as one which depends on the number of solute
particles in solution and not in any way on the size or
chemical nature of the particles.
- It show only for dilute solutions. (Solids in liquids)
- Depends on number of particles in solutions.
- Used for finding the molecular weights of the dissolved
substances.
• Properties
1. Lowering of vapor pressure
2. Elevation of boiling point
3. Depression of freezing point
LOWERING OF VAPOR PRESSURE : Raoult’s Law (I st way)
Derivation of Raoults Law:
 LOWERING OF VAPOR PRESSURE
Raoult’s Law (II nd Way)
“The partial pressure(Pi/Pii)of each component in a
solution is equal to the mole of
component fraction & the
component” vapour pressure the the
of
Pi = P1X1 Or Pii= P2X2 pure
P = P1X1 + P2X2

74
 Raoults Law: By Graphically

Vapor Pressure Vs Composition curve

Vapour
Pi
V.P.P=Pi+Pii
Pressure

Pii Pi=P1X1

Pii=P2X2

Composition
 IDEAL SOLUTIONS
“ Solutions which obey Raoult’s law in all the
solute composition in a solvent” (Ideal
Solution)

76
 Deviation from Raoults Law: Real Solution
“Solutions which do not obey Raoult’s law over entire range of composition”
The non ideal or real solution show either positive or negative deviation from
ideal behaviour.
Negative Deviation :
•V.P. of the solution is less than that calculated using Raoults law. Because of
attractive forces of molecule.
•V.P. of liquid depends on escaping tendency of a liquid.
•Greater the escaping tendency greater is V.P. of the liquid.
•Escaping tendency of the solvent decreases due to addition of solute then
system shows negative deviation.
Ex. Chloroform & acetone
Negative deviation
PA < Xa P
△H < 0
△V < 0
 Positive Deviation:
The escaping tendency of the liquids increases.
The presence of the molecules of solute results in the
decrease in the force of attraction between the molecules of
the solvent.
Thus increasing the escaping tendency of the solvent &
hence increase in V.P.
The observed V.P. of the solution is more than that is
expected from Raoults law. Ex. Benzene and ethyl alcohol

Positive deviation
PA > Xa P
△H > 0
△V > 0
14
 Phase Rule & Partially Miscible Liquids

PHASE RULE
• It was first presented by Gibbs in 1875.
•It is very useful to understand the effect of intensive
variables, such as temperature, pressure, or
concentration, on the equilibrium between phases as
well as between chemical constituents.
• It is used to deduce the number of degrees of
freedom
(f) for a system. Sometimes called: “the variance of the
system”.
Gibbs Phase rule
Phase rule is a device for relating the effect of the least
number of independent variables (examples are
temperature, pressure & concentration) upon the
various phases that can exist in equilibrium system
containing a given number of components.
Mathematically,
F=C-P+2
Where, F= number of degree of freedom
C= number of components
P= number of phases
 Condensed Phase rule
If the equilibrium between various phases is
unaffected by the pressure then the degree of
freedom will have to be reduced by one.
Mathematically,
F=C-P+1
Where, F= number of degree of freedom
C= number of components
P= number of phases
It is also called as reduced phase rule.

Ex. Phenol-water system.

 Applications of Phase Rule
1. Phase rule can be applied in determining the purity of a
substance.
2. From phase diagram observing weather the system in
liquid, solid or gaseous state.
3. Observing the system would be a 3/2/1 phase system at
particular temp.
4. Also help to formulate a stable formulation.
5. Selecting the experimental conditions.
6. Improve the solubility of substances.
7. Reducing the aggregation.
8. Helpful in solvent extraction technique.
 PHASE: (P)
A phase is defined as a homogeneous and physically
distinct part of a system having all physical and
chemical properties the same throughout the system.
A system may consist of one phase/more phase,
physically distinct & separated by boundary…
E.g.
 A system containing only liquid water/pure substance is
one-phase system; P=1.
 A system containing liquid water and water vapour
(gas) is a two phase system; P=2.
 A system containing liquid water, water vapour and
solid ice is a three phase system; P=3.
• Pure substances (solid, liquid, or gas) made of
one chemical species only, is considered as one
phase;
Substance Comments Phases (P)
Oxygen gas Homogeneous 1
Liquid benzene Homogeneous 1
Mix of water & alcohol Miscible liquids 1
Mix of water & oil Heterogeneous 2
Solution of NaCl in water Homogeneous 1
Mix of ice-water-water vapour Heterogeneous 3
 COMPONENT:(C)
The term number of components is defined as the
smallest number of independent constituents by
which the compositions of each phase in the system
can be expressed in the form of a chemical formula or
equation, at equilibrium.
E.g.
 Water system has three phases, ice, water and water
vapour and the composition of all these phases is
expressed in terms of one chemical individual water.
Thus water system has one component only.
 Similarly Sulphur system has four phases: rhombic
sulphur, monoclinic sulphur liquid sulphur and sulphur
vapour and the composition of all these phases is
expressed by one chemical individual sulphur. Therefore
Sulphur system is one component system.
Thus, all the phases in one component system is
expressed by only one chemical individual.
 A saturated solution of NaCl in contact with
excess solid NaCl has two phases. The
composition of both the phases can be expressed
in terms of two chemical individual NaCl and water.
Hence a saturated solution of NaCl in water in
contact with excess solid NaCl is a two component
system.

• DECOMPOSITION OF CALCIUM CARBONATE

CaCO3(s)= CaO(s) + CO2(g)

It has three phases but the composition of the system can be
expressed in terms of two of the three chemical substances in
equilibrium. Hence it is a two component system
 • Dissociation of NH4Cl
NH4Cl(s) = NH3 (g) + HCl (g)
 Ammonium chloride when heated in a closed vessel
dissociates into ammonia and HCl gas. The system
consists of two phases solid NH4Cl and gaseous mixture
containing NH3 and HCl However the constituents of
the mixture are in the same proportion in which they
are combined in solid NH4Cl. The composition of the
both the phases therefore be expressed in terms of the
same chemical individual NH4Cl. Thus the dissociation
of NH4Cl is one component system.
 Mixtureof oxygen & nitrogen
The composition of N & O is gaseous form. It
homogeneous mix so one phase and two component
system.
 Degrees of Freedom(F)
It is defined as the least number of variable factors of a system
such as temp., pressure, conc., R.I., density, viscosity that
must be fixed to describe the system completely.
The number of degree of freedom is the least number of
intensive properties.(does not depend on size or amount of material)
E.g. System Degree of freedom Intensive properties
Pure gas F= 1-1+2=2 Pressure & volume or
Bivariant Volume & temp.
Or Pressure & temp.
Mixture of two gases F=2-1+2=3 Pressure, temp., conc.
Trivariant
Water & water vapor F=1-2+2=1 Vapor pressure or temp.
in equilibrium Mono or Univariant
Saturated solution of F=2-3+2=1 Pressure
NaCl with Mono or Univariant
undissolved solid &
vapor

Ice-water-water F=1-3+2=0 No
vapor In or nonvariant
 Advantages of Phase Rule
• Phase rule is applicable to both Chemical and Physical
equilibria.

•Phase rule is applicable to macroscopic systems and hence no

information is required regarding molecular or micro structure.

•We can conveniently classify equilibrium states in terms of phases,

components and degrees of freedom.

• The behaviour of system can be predicted under diff. conditions.

•According to phase rule, diff. systems behave similarly if they have

same degrees of freedom.

• Phase rule helps in deciding under a giving set of conditions:

1) Existence of equilibrium among various substances.
2) Interconvergence of substance
3) Disappearance
or of some of the
substances.
 Limitations of Phase Rule

•Phase rule is applicable only for those systems which are in

equilibrium. It is not much use for those systems which attain the
equilibrium state very slowly.

•Only three degrees of freedom viz, temperature, pressure and

concentration are allowed to influence the equilibrium systems.

•Under the same conditions of temperature and pressure, all the

phases of the system must be present.

•It considers only the number of phases, rather than their

amounts.
 Phase Rule in One-Component System
Phase diagram is a plot of showing the conditions of
pressure & temp. under which two or more physical states
can exist together in equilibrium.
These diagram also known as
P-T diagram.

One-component systems-
Ex. Water
Phase diagram of water consist of
• Regions or areas
• Lines or curves
• Triple point
A. Regions or areas: In phase diagram
• 3 regions
• COB-solid ,AOB-liquid, COA-Vapor state
• Apply Phase Rule:
• F =C-P+2 =1-1+2=2 Bivarient (P&T)

• B. Lines or curves: In phase diagram 3

lines
• OA=Vaporization curve
• OB=Melting or fusion curve
• OC= sublimation curve
• Above & below single phase;
• on line two phases at equilibrium
• F =C-P+2 =1-2+2= 1Univarient (P or T)
• C. Triple point:
• The three boundary lines
intersect at a common point
called triple point.
• ie. shows all three phases co exist
in equilibrium.
• F =C-P+2 =1-3+2=0 non-varient.

• Applications:
• Used in selecting the
experimental conditions in freeze
drying of drugs like Biologicals,
vaccines, sera & antibiotics etc.
 Partially Miscible Liquids in Two Component system
• Partially miscible liquids are defined as a two liquid
system in which their mutual solubility in one another is
limited.
• When Temp. Increased --- mutual solubility of one liquid
in another increases.
• It also called as conjugate liquids.
• Miscibility temp. is defined as temp at which two
conjugate solutions are mutual soluble.
• Miscibility temp identified by disappearance or
reappearance of turbidity.
• Critical solution temp. is defined as a temp. at which two
phases exist at equilibrium.
 Phenol and water system phase diagram.

Temperature fixed at 50 °C

Point a, system containing

100% pure water.

Addition of phenol to water will

result in the formation of a single
liquid phase until the point b is
reached.

At point b, appears a second

phase.

Phase A: water rich phase

containing 11% phenol

Phase B: phenol rich phase 7

containing 63% phenol

  increasing quantities of
phenol,
i.e., as we proceed across the
diagram from point b to point c,
we form systems in which the
amount of the phenol-rich phase
(B) continually increases.

 At the same time the

amount. of the water-rich
phase (A) decreases.
Once the total conc. of phenol
exceeds 63 % at 50
0C a single phenol-rich
liquid phase is formed. 8
 At 50°C
Aqueous phase saturated with phenol:
contains 11% phenol (point b)

Phenolic phase saturated with water:

contains 63% phenol (point c)

9
 The line bc drawn across the
region containing two phases
is termed a tie line; it is
always parallel to the base
line in two component
systems.

 all systems prepared on a

tie line at 50° C will
separate into phases of
constant composition
whose composition is b and
c. These phases are
termed conjugate phases.
10
11
 Applying the phase rule show that
In the phase diagram of Phenol water system
Above the curve- One phase (Reduced Phase rule)
F=C-P+2 F=C-P+1
F=2-1+2=3 F= 2-1+1=2
P is fixed & other Temp & conc.
T , conc.

Below the curve- Two phase (Reduced Phase rule)

F=C-P+2 F=C-P+1
F=2-2+2=2 F= 2-1+1=1
P is fixed & other Temp or conc.
T or conc.
 TRIETHYLAMINE & WATER
The solubility of liquid
pairs may increase as
the temperature is
lowered
The system will exhibit
a
lower consolute temp.
Below which the two
members are soluble in
all proportions
Above
separatewhich two
layers are 14

formed.
 NICOTINE & WATER

280
Mixtures such as nicotine & 1 phase upper CST
water show both an upper and 208

220
a lower consolute

Temperature (°C)
160
2 phases
temperature
with an intermediate

100
61 lower CST

temperature region in which 1 phase

40
the two liquids are only
0 20 40 60 80
partially miscible.

0
100
Nicotine in water
% by weight
4. Systems with no critical solution temperature
The pair, ethyl ether and water, has neither an upper nor a
lower consolute temperature and shows partial miscibility15
over the entire temperature range at which the mixture
Critical solution temperatures are very sensitive to
impurities or added substances.
The addition of a substance to a binary liquid system
produces a ternary system.

16
17
18
 Phase Equilibria in
Three component systems
Three component systems containing one pair of
partially miscible liquids
Water & benzene are partially miscible
• Alcohol is completely miscible with both

• Addition of sufficient alcohol gives

one phase system in which all the 3
components are miscible (alcohol Benzene saturated
with water
acts as heat in phenol water system)
• It breaks cohesive force between water saturated
mol. with Benzene
26
 3 components & one phase
In non condensed system
F=C–P+2 F may be:
F = 3 - 1+ 2 = 4 1- T 2- P 3,4 – conc of 2 C
conc of the third component =
total conc - sum of 2 comp. conc.

In condensed system and constant temp

F=C–P+0
F = 3 – 1 + 0 = 2 (conc of 2 component) B

1
phase
2 d e
i
f phases
a 2
A c
C
 The area within the triangle B
represents all the
possible combinations of A, B,
and C to give three component
systems.
 The location of a particular
three component system x
within the triangle, e.g. point x
A C
may be undertaken as follows:
 The line AC, opposite apex B , represents systems,
containing A and C. B is absent, i.e., B.= 0 .
 The horizontal lines running across the triangle parallel to
AC indicate increasing percentages of B from B = 0 (on
line AC) to B = 100 (at point B).
 The line parallel to AC which cuts point x is equivalent to
15 % B; consequently, the system contains 15 percent of B
and 85 percent of A and C together. 29
 B
Applying similar arguments to
the other two components in the
system, we can say that along the
line AB, C=0.

 As we proceed from the line AB

towards C across the diagram, the
concentration of C increases until
at the apex, C = 100 percent. A C

 The point x lies on the line parallel to AB, that is

equivalent to 30 percent of C.
Therefore the concentration of A is
100 - (B + C) = 100 - (15 + 30) = 55 per cent.

30
 A=0%
B 100%
C=0%

30
q
Increasing C
Increasing B

20 r

h p C 100%
100% A 50
B=0%
Increasing A A=0%
 B

1 phase

d
e
2 phases
i
f
a c
A C
 B

1 phase

d
e
2 phases
i
f g h
a c
A C
Tie line fi
 Systems g and h prepared along the tie line fi both rise to two
phases having the compositions denoted by the points f and i.
 For example, system g, after reaching equilibrium, will
separate into two phases, f and i. The ratio of phases f to
phase i, on a weight basis, is given by the ratio gi : fg.
32
 NERNS’T DISTRIBUTION LAW
( PARTITION COEFFICIENT)
The movement of molecules from one phase to is called
another
partitioning.
• If two immiscible phases are placed adjacent to each other, the solute will
distribute itself between two immiscible phases until equilibrium
is
attained; therefore no further transfer of solute occurs.

• When a substance is added in excess quantity in two immiscible solvents,

it distributes itself between two liquid phases so that each becomes
saturated.

• The distribution or partition of a solute between immiscible liquids is

known as Nernst’s distribution law or simply distribution law or
partition law.
• Nernst’s distribution law states that when the added
substance is insufficient to saturate the immiscible liquids,
the solute distributes between the liquids in such a way that
at equilibrium the ratio of concentrations of the solute in the
two liquids is constant, at constant temperature.

• Partition(P) or distribution coefficient(D) is the ratio of

concentration of a compound in the two phases of a mixture
of two immiscible solvents at equilibrium
• Hence these coefficients are a measure differentia
of solubility of the compound between two l

• solvents.
One of the solvents is water and the second one is
hydrophobic such as octanol. It is useful in estimating the
distribution of drugs within the body.

• It is the ratio of concentration of a substance in organic

phase to the concentration of substance in aqueous phase
at constant temperature.
It is given as:
Equilibrium constant, 𝐾 = 𝐶𝑜
𝐶𝑤

Where, K= Partition coefficient/ distribution

coefficient/ distribution ratio.

Co= Equilibrium concentration of substance

in
organic phase.

Cw= Equilibrium concentration of substance in

aqueous phase.
 Partition Coefficient (P)
• Partition coefficient (P) is a parameter that characterizes the
relative affinity of a compound in its unionized form for water
and an immiscible model lipid solvent (octanol).
• Octanol was chosen as the model lipid phase because it
most closely
simulates the properties of biological membranes.
• Determination of P (or log P) values involves the
placing of a drug compound along with the two immiscible
solvents in a separation funnel.
• Molecules of the solute will distribute in each phase
until
equilibrium is established.
• The ratio of the two concentrations is the partition
coefficient or
distribution coefficient P, i.e. P = Co /Cw. 13
The partitioning of a drug molecule between two phases
can be quantified by a partition coefficient

‘p’=SA/SB
In which
SA means solubility of a compound in
phase A SB means solubility of a
compound in phase B
 The org.phase usally chloroform and
aq. Phase usally water
 Divided conc of org.phase and
aq.phase.
 General Features:

• Drugs partition between the aqueous phase and

lipophilic
themselves membrane.
• If the partition coefficient of drug is more than one it is more lipophilic

• If the partition coefficient of drug is less than one it is less lipophilic.

• It is a measure of how well substance partitions between lipid and water.

• Hydrophobic drugs with high partition coefficients are preferentially

distributed
• to hydrophobic compartments such as bilipid layers of cells.
• Hydrophilic drugs with low partitioncoefficient are found in
hydrophilic compartments such as blood serum.
 Log p -1.0 0 1.0 2.0 3.0 4.0 5.0
6.0

Polar compounds Compound of Non polar compounds

intermediate polarity
Good aq. Solubilty Poor aq. Solubility
Good balance
Poor liquid solubility between aq. And lipid Good lipid solubility
solubility.
Poor adsorption and Slow excretion
distribution. Good absorption and
distribution.

Fig:Effect of log p values on solubility absorption and distribution

of
drug sunstances.
 Partition Coefficient (P)
Interpretation
• P > 1 or Log P > 0 implies that the drug has
affinity for lipid membranes
• P = 1 or Log P = 0 there is equal distribution
between the water and oil layer.
• P < 1 or Log P < 0 the drug has affinity for water
or hydrophilic layer.
• Structure affect the value of partition coefficient
P
• Thesubstituent that increase P value are -alkyl, -aryl, -
halogens
• The substituent that decrease P value are -COOH, -
NH2, -O, -CO , -OH
Limitations:

• Dilute solutions: The conc. of solute must be low in two solvents. This
law does not holds good when the concentrations are high.

• Constant temperature: Temperature should be kept constant

throughout
the experiment, since solubility is dependent on temperature.

• Same molecular state: Solute must be in the same molecular state in

both the solvent. This law does not hold, if there is association or
dissociation of solute molecules in one of the solvents.

• Equilibrium concentration: This is achieved by shaking the mixture for

longer time.

• Non-miscibility of solvents: So, the solvents are to be allowed for

separation for a sufficient time.
• The lipophilicity of an organic compound is usually described in
terms of a partition coefficient, log p, which can be defined as
the ratio of the concentration of the unionized compound, at
equilibrium, between organic and aqueous phases:
DISTRIBUTION COEFFICIENT or logD:

It is the ratio of sum of the concentrations of all forms of the

compound in each of the two phases.

To measure distribution coefficient, the pH of the

aqueous phase is
buffered to specific value.
• The situation is more complex with drugs that ionise in aqueous
solution – and that is most of them. These drugs are
characterised by their distribution constant, D. Its value
depends on pH.
Where

[Drug molecule]o = concentration of drug in its molecular form in

octan-1-ol;

[Drug molecule]w = concentration of drug in its molecular form

in
water;

[Drug ion]w = concentration of drug in its ionised form in water.

 MEASUREMENT OF PARTITION COEFFICIENT:

It can be measured by using following methods.

• Shake flask (or tube) method.
• HPLC method.
• Electrochemical method.
• Slow-Stirring Method.
• Estimation method based on individual
solubilities.
Shakeflask method:
• common method.
• some amount of drug is added, dissolved in octanol & water.
• The distribution of solute is measured by two methods.
i. UV-Visible spectroscopy
ii. Carrier free radiotracer
UV-Visible spectroscopy:

• In this method, after dissolving the drug between two

phases, they are separated.

• Standard dilutions are prepared.

• The absorbance is measured at suitable wavelength.

• By using calibration curve, the concentration of the
sample in both organic and aqueous phase can be
measured.
Advantages of shake flask method:

• Most accurate method.

• Accurate for broadest range of solutes(neutral or charged compounds).

• Chemical structure does not have to be known beforehand.

Disadvantages:

• Time consuming(>30min per sample)

• Octanol and water must be mixed and equilibrated(takes 24hours)

• Complete solubility must be attained and it is difficult to detect

small amounts of undissolved material.

• Large amounts of material are required.

Carrier free Radiotracer:
• In this method a known amount of a radioactive material is added to
one of the phases.

• The two phases are then brought into contact and mixed until
equilibrium has been reached. Then the two phases are separated
before the radioactivity in each phase is measured.

Disadvantage:
• The solute can absorb on the surfaces of the glass (or plastic)
equipment or at the interface between the two phases. To guard
against this the mass balance should be calculated.
HPLC method:
• By correlating its retention time with similar compounds with
known
logP values.

• HPLC is performed on analytical columns packed with a commercially

available solid phase containing long hydrocarbon chains (e.g. C8, C18)
chemically bound onto silica.

• Mixtures of chemicals are eluted in order of their hydrophobicity, with

water-soluble chemicals eluted first and oil-soluble chemicals last.

• This enables the relationship between the retention time on

such a
(reverse phase) column and the n-octanol/water partition coefficient.
Advantages:

• Fast method of determination (5-20 min per sample).

Disadvantages:

• The solutes chemical structure must be known beforehand.

• Since the logP value is determined by linear regression, several

compounds with similar structures must have known logP
values.
Electrochemical method:
In this polarized liquid interfaces have been used to
examine the thermodynamics and kinetics of charged species
from one phase to another.

Two methods exist:

ITIES, between two immiscible
interfaces electrolyte
solutions.
Droplet experiments – here a reaction at a triple interface
between a conductive solid, droplets of a redox active liquid
phase and an electrolyte solution- used to determine the energy
required to transfer a charged species across the interface.
Slow-Stirring Method: -

• More recent method developed as an alternative to the shake

flask procedure.

• Emulsion formation will be reduced.

• Requires a few days to reach equilibrium.

•Difficult to adapt to a high throughput approach.

Radiolabelled substances – which may be synthesized for use

in other tests – can be very useful for accurate log
Kow determination.
Estimation method based on individual solubilities: -

• Based on the ratio of the solubility of the material in octanol and

water.
• For some substances (e.g. some surfactants and pigments) it is
technically not feasible to measure an octanol-water partition
coefficient.

• For such substances it may be possible to obtain a ratio of the

saturated water solubility and saturated octanol solubility.
• It does not include the interaction between the water and solvent
phase (i.e. a substance with high Kow is rather 'pushed out of the
water' than 'pulled into octanol").
• This explains the poor correlation typically observed between
octanol solubility and Kow.

• The ratio was found to be somewhat more representative if one

uses octanol/saturated water and water/saturated octanol.

• As such, a ratio estimation would be a less preferred yet

acceptable alternative for the octanol/water partition coefficient
(Kow), but must be treated with caution as it would not have
been derived in the same manner as other KowS.
 Some octanol-water partition coefficient data:

Component logPo/w Temperature

Acetamide -1.16 25
Methanol -0.82 19
Formic acid -0.41 25
Diethyl ether 0.83 20
P-dichlorobenzene 3.37 25
Hexamethyl benzene 4.61 25
2,2’,4,4’,5-pentachlorobiphenyl 6.41 Ambient
Applications:

• Solubility of drugs in water and other solvents and in mixture of

solvents can be predicted.

• Drug absorption in vivo can be predicted.

• The oil-water partition coefficients are indicative of
lipophilic hydrophilic character of drug molecules.

• Structure activity relationship (SAR) for a series of drugs can be

studied.
• Extraction: Drugs from biological fluids such as blood, tissue
and urine can be extracted efficiently by the principle of
Multiple Extraction.

• Emulsions: Effective concentration of preservative can be

established for the storage of emulsion and other dosage
forms.

• Release of drugs from ointments and creams can be predicted.

• Partition principle is used in partition chromatography to separate
organic substance from mixtures.

• Complexation: Certain complexes partition difficulty to the

substrate and complexing agent. This change in lipophilicity will
affect the activity of the drug and can also be used to measure the
extent of complexation.

• Chemical modification: Chemical changes related to lipid

solubility and its effect on GI absorption are best exemplified by
barbiturates,
• Metallurgy: In metallurgy, the partition coefficient is an important
factor in determining how different impurities are distributed between
molten and solidified metal.

• Agrochemicals: Hydrophobic insecticides and herbicides tend to be

more active. Hydrophobic agrochemicals in general have longer half
lives and therefore display increased risk of adverse environmental
impact.

• Pharmacokinetics: In pharmacokinetics, the distribution coefficient has

a strong influence on ADME properties of the drug. More specifically, in
order for a drug to be orally absorbed, it normally must first pass
through lipid bilayers in the intestinal epithelium. For efficient transport,
the drug must be hydrophobic enough to partition into the lipid bilayer,
but not so hydrophobic.
• Pharmacodynamics: In this the hydrophobic effect is the major
driving force for the binding of drugs to their receptor targets. On
the other hand hydrophobic drugs tend to be more toxic because
they retained longer and have wider distribution within the body.
Hence it is advisable to make the drug as hydrophilic as possible so
the ideal distribution coefficient for a drug is usually intermediate.

• Like, preservative emulsions partition between the water and oil

phases; antibiotics partition from body fluids to microorganisms;
and drug and other adjuvants can partition into the plastic and
rubber stoppers of the containers. It is therefore is important that
this process is understood.
 Drugs pKa pH/site of absorption
Very weak acids (pKa > 8.0)
Phenobarbital 8.1 Unionised at all pH values;
Hexobarbital 8.2 absorbed along the entire
Phenytoin 8.2 length of GIT.
Moderately weak acids (pKa 2.5 to 7.5)
Cloxacillin 2.7 Unionised in gastric pH
and
Aspirin 3.5 ionised in intestinal pH; better
Ibuprofen 4.4 absorbed from the stomach.
Stronger acids (pKa < 2.5)
Disodium cromoglycate 2.0 Ionised at all pH values; poorly
absorbed from GIT.
Very weak bases (pKa< 5.0)
Theophylline 0.7 Unionised at all pH values;
Caffeine 0.8 absorbed along the entire
Diazepam 1.7 length of GIT.
Moderately weak bases (pKa 5 to 11.0)
Reserpine 6.6 Ionised at gastric pH, relatively
Codeine 8.2 unionised at intestinal
pH;
Amitriptyline 9.4 better absorbed from intestine.

Stronger bases (pKa > 11)

Mecamylamine 11.2 Ionised at all pH values; poorly
 Refere
nce
• Sinko, Martin's physical pharmacy and
pharmaceutical sciences: physical chemical and
biopharmaceutical principles in the pharmaceutical
sciences, Philadelphia, Lippincott Williams &
Wilkins.
THANK YOU…..

147